Protective Effects of Intranasally Administrated Oxytocin-Loaded Nanoparticles on Pentylenetetrazole-Kindling Epilepsy in Terms of Seizure Severity, Memory, Neurogenesis, and Neuronal Damage.

Pentylenetetrazole (PTZ)-induced kindling is an animal model for studying human temporal lobe epilepsy (TLE), which is characterized by alterations of hippocampal neurons and memory. Although the intranasal (IN) administration of oxytocin (OT) has limited efficiency, nanoparticles (NPs) are a promising candidate to deliver OT to the brain. However, there are very limited data on epilepsy research about oxytocin-loaded nanoparticles (NP-OTs). The aim of this study is to investigate the effects of IN administration of chronic NP-OTs on the hippocampus of PTZ-induced male epileptic rats in terms of seizure severity, memory, neurogenesis, and neuronal damage. Saline/OT/NP-OTs were administrated to both control (Ctrl) and PTZ groups intranasally. Consequently, saline and PTZ were injected, respectively, 25 times every 48 h. Then, seizure severity (score and latency) was calculated for the PTZ groups. A spatial working memory evaluation test (SWMET) was performed after the last injection. Hippocampus histopathology, neurogenesis, and apoptosis were demonstrated. Serum total antioxidant status (TAS) and total oxidant status (TOS) levels and the oxidative stress index (OSI) were measured. We showed that OTs and NP-OTs prevented the kindling development and had positive effects on seizure severity. SWMET-related behaviors were also recovered in the PTZ + NP-OT group. A significant increase of neurogenesis and decrease of apoptosis in the hippocampus of the PTZ + NP-OT group were observed, while OTs and NP-OTs had protective effects against PTZ-induced damage to hippocampal neurons. Our results indicate that the chronic administration of NP-OTs may have positive effects on hippocampal damage via increasing neurogenesis and decreasing apoptosis and seizure severity.

Scorpion Envenomation of Lactating Rats Decreases the Seizure Threshold in Offspring.

Few data are available in the literature describing the long-term effects of envenoming in the perinatal period. In this study, the relationship between envenoming of lactating rats and possible behavioral changes in the mother and in her offspring were investigated. Lactating Wistar rats received a single dose of T. serrulatus crude venom on postnatal days 2 (V2), 10 (V10) or 16 (V16), and had their maternal behavior evaluated. The seizure threshold was evaluated in adulthood offspring. A decrease in maternal care during envenoming was observed in V2 and V10 groups. The retrieval behavior was absent in the V2 group, and a lower seizure threshold in the adult offspring of all groups was observed. During envenoming, mothers stayed away from their offspring for a relatively long time. Maternal deprivation during the early postnatal period is one of the most potent stressors for pups and could be responsible, at least in part, for the decrease in the convulsive threshold of the offspring since stress is pointed to as a risk factor for epileptogenesis. Furthermore, the scorpionic accident generates an intense immune response, and inflammation in neonates increases the susceptibility to seizures in adulthood. Therefore, maternal envenoming during lactation can have adverse effects on offspring in adulthood.

Resveratrol loaded nanoparticles attenuate cognitive impairment and inflammatory markers in PTZ-induced kindled mice.

Resveratrol has been found to exert protective effects in neurological disorders, including epilepsy. However, its poor bioavailability and difficulty in reaching the brain's targeted location reduce resveratrol's efficacy substantially. The side effects due to the higher concentration of drugs are another matter of concern. The objective of the present study is to propose solutions to these issues by encapsulating resveratrol in glutathione-coated collagen nanoparticles' core. The collagen nanoparticles increase the resveratrol's bioavailability, and glutathione helps in the passage of the encapsulated resveratrol to the target location in the brain. The concentration also substantially reduces due to resveratrol's encapsulation in glutathione-coated collagen nanoparticles. The encapsulated resveratrol is termed nanoresveratrol. The effectiveness of nanoresveratrol on epilepsy seizures was evaluated through histopathological examinations, ELISA tests, and qRT-PCR tests on the hippocampus of the kindled mice. The novelty of the present study thus lies in (i) the synthesis of nanoresveratrol using glutathione-coated collagen nanoparticles and (ii) the application of synthesized nanoresveratrol in the treatment of epilepsy. The study's outcome shows that nanoresveratrol has a favorable impact in reducing cognitive impairment in kindled mice, and it is more effective in controlling epilepsy seizures than resveratrol. The p-values of all the nanoresveratrol-given groups of mice (compared with the diseased group) were substantially smaller (∼10-4 to 10-2) than the significance level (0.05), indicating that the nanoresveratrol-given groups are significantly different from the diseased group, i.e., the nanoresveratrol has a significant effect on the mice. The concentration of resveratrol also decreases substantially in the proposed nanoformulation. It was observed that even 0.4 mg/kg of nanoformulation of resveratrol is performing better than 40 mg/kg of resveratrol.

Morphological changes in the substantia nigra pars reticulata of the mice during kindling.

Substantia nigra pars reticulata (SNpr) has been implicated in modulation, propagation and cessation of seizures. This study aimed to determine whether structural changes occur in SNpr during kindling. Male mice were randomly divided into four groups including early and late-phase kindled groups and their time-matched controls. Kindling was induced by every other day administration of a subconvulsive dose of PTZ (40 mg/kg, i.p.). The first occurrence of seizure behaviors was used to categorize the early and late phases of kindling. There was no significant difference in the volume of SNpr between the early- and late-phase kindled groups. The diameter of SNpr was significantly increased in the early phase group and decreased in the late phase group as compared to their matched controls (p < 0.05). Reduced neural cells and increased dead cell numbers were observed in the SNpr of the late-phase group in comparison to its control group (p < 0.05). These findings suggest that SNpr is a sensitive and vulnerable structure involving seizure propagation in the processes of epileptogenesis.

In vivo screening and toxicity studies of indolinone incorporated thiosemicarbazone, thiazole and piperidinosulfonyl moieties as anticonvulsant agents.

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.

Rhein attenuates PTZ­induced epilepsy and exerts neuroprotective activity via inhibition of the TLR4-NFκB signaling pathway.

BACKGROUND: Epilepsy is a common neurological disease that cannot be well controlled by existing antiepileptic drugs. Studies have implicated oxidative stress and inflammation in the pathophysiology of epilepsy. Rhein has a comprehensive pharmacological function in reducing inflammation and can play a neuroprotective role in many neurological diseases, however little is known about its effects on epilepsy. METHODS: A model of acute epilepsy in mice was established using the Pentylenetetrazol (PTZ) ignition method to evaluate the effects of Rhein on the duration and latency of convulsions, and the number and severity of seizures. Modified Neurological Severity Score (mNSS), Rotarod and open-field behavioral task tests were performed to evaluate the neuroprotective effect of Rhein. TUNEL staining was used to assess neuronal damage, and western blot, qPCR and ELISA kits were utilized to determine the expression of inflammatory signaling protein molecules and levels of inflammatory cytokines. RESULTS: In this study, we demonstrate that Rhein delayed the onset of seizures, decreased their severity, and reduced the duration and frequency of seizures in PTZ-induced epileptic mice. Furthermore, we found that Rhein blocked neurological deficits induced by PTZ. In addition, our results show that Rhein inhibited the activation of the TLR4-NFκB signaling pathway and decreased the secretion of the inflammatory cytokines TNF-α, IL-6, IL-1ß, and IL-18. CONCLUSION: Our results suggest that the anticonvulsant and neuroprotective effects of Rhein are achieved by disrupting the processes involved in PTZ acquisition of epilepsy.

Pentylenetetrazol-induced seizures in adult rats are associated with plastic changes to the dendritic spines on hippocampal CA1 pyramidal neurons.

Epilepsy is a chronic neurobehavioral disorder whereby an imbalance between neurochemical excitation and inhibition at the synaptic level provokes seizures. Various experimental models have been used to study epilepsy, including that based on acute or chronic administration of Pentylenetetrazol (PTZ). In this study, a single PTZ dose (60 mg/kg) was administered to adult male rats and 30 min later, various neurobiological parameters were studied related to the transmission and modulation of excitatory impulses in pyramidal neurons of the hippocampal CA1 field. Rats experienced generalized seizures 1-3 min after PTZ administration, accompanied by elevated levels of Synaptophysin and Glutaminase. This response suggests presynaptic glutamate release is exacerbated to toxic levels, which eventually provokes neuronal death as witnessed by the higher levels of Caspase-3, TUNEL and GFAP. Similarly, the increase in PSD-95 suggests that viable dendritic spines are functional. Indeed, the increase in stubby and wide spines is likely related to de novo spinogenesis, and the regulation of neuronal excitability, which could represent a plastic response to the synaptic over-excitation. Furthermore, the increase in mushroom spines could be associated with the storage of cognitive information and the potentiation of thin spines until they are transformed into mushroom spines. However, the reduction in BDNF suggests that the activity of these spines would be down-regulated, may in part be responsible for the cognitive decline related to hippocampal function in patients with epilepsy.

Neurochemical Effects of 4-(2Chloro-4-Fluorobenzyl)-3-(2-Thienyl)-1,2,4-Oxadiazol-5(4H)-One in the Pentylenetetrazole (PTZ)-Induced Epileptic Seizure Zebrafish Model.

Epilepsy is one of the most common neurological disorders, and it is characterized by spontaneous seizures. In a previous study, we identified 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as a novel anti-epileptic agent in chemically- or genetically-induced epileptic zebrafish and mouse models. In this study, we investigated the anti-epileptic effects of GM-90432 through neurochemical profiling-based approach to understand the neuroprotective mechanism in a pentylenetetrazole (PTZ)-induced epileptic seizure zebrafish model. GM-90432 effectively improved PTZ-induced epileptic behaviors via upregulation of 5-hydroxytryptamine, 17-ß-estradiol, dihydrotestosterone, progesterone, 5α -dihydroprogesterone, and allopregnanolone levels, and downregulation of normetanephrine, gamma-aminobutyric acid, and cortisol levels in brain tissue. GM-90432 also had a protective effect against PTZ-induced oxidative stress and zebrafish death, suggesting that it exhibits biphasic neuroprotective effects via scavenging of reactive oxygen species and anti-epileptic activities in a zebrafish model. In conclusion, our results suggest that neurochemical profiling study could be used to better understand of anti-epileptic mechanism of GM-90432, potentially leading to new drug discovery and development of anti-seizure agents.

Stimulatory and inhibitory effects of morphine on pentylenetetrazol-induced epileptic activity in rat.

AIMS: The present study attempts to evaluate the effects of different doses of morphine on experimental epileptiform activity caused by pentylenetetrazol (PTZ) in rats. METHODS: Thirty adult male rats were assigned to saline (n = 5), morphine (2, 5, and 10 mg/kg, n = 15), naloxone (1 mg/kg, n = 5), and pre-treated with naloxone+morphine (1 + 10 mg/kg, n = 5) groups. The animals were anesthetized with ketamine + xylazine (80 + 8 mg/kg), and then a bipolar electrode was implanted into the CA1 (AP: -2.76 mm, ML: -1.4 mm and DV: 3 mm). To evaluate the effects of drugs on spike count and their amplitudes by elab amplifier, after drug administration for 25 min, PTZ (80 mg/kg, i.p.) was injected to induce epileptiform activity. Finally, diazepam (10 mg/kg) was used to suppress epileptic activity. RESULTS: The results revealed that morphine at a dose of 2 mg/kg decreased, and at doses of 5 and 10 mg/kg had an increasing effect on seizure-like events (SLEs). Nevertheless, morphine at a dose of 10 mg/kg enhanced SLEs significantly (p < 0.01). Naloxone at a dose of 1 mg/kg had no significant effect on the spike count but increased amplitude of them (p < 0.001). Moreover, being pretreatment with naloxone at a dose of 1 mg/kg, the morphine group showed significantly increased in the spike count (p < 0.05). CONCLUSIONS: Morphine has biphasic effects on PTZ-induced epileptiform activities that way at a low dose has an inhibitory effect, but if the dose is increased, it will intensify the desired event and that the stimulatory effects of morphine appear not to be via opioid receptors.

Neuroprotective role of chrysin-loaded poly(lactic-co-glycolic acid) nanoparticle against kindling-induced epilepsy through Nrf2/ARE/HO-1 pathway.

Chrysin is the major bioactive compound of blue passionflower, an important medicinal plant used in traditional herbal formulations since ancient times. In the present study, we report that chrysin nanoparticles (chrysin NPs) protect Wistar rats against kindling-induced epilepsy. Nanoparticles of sizes less than 150 nm with a spherical shape were prepared using poly(d,l-lactic-co-glycolic acid) and polyvinyl alcohol, respectively, as polymer and stabilizer. Rats were injected with subconvulsive doses of pentylenetetrazole (PTZ) (35 mg/kg, intraperitoneal) every second day, with 22 injections in total, and on the same days, they received protective doses of the chrysin NPs (5 and 10 µg/mL, PO), respectively, 45 min before each PTZ injection. After the last PTZ injection, an average of thirteen seizure scores was recorded. Animals were killed by decapitation 24 h after a seizure. The cortex and hippocampus were removed and stored in liquid nitrogen for determining oxidative stress terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, histopathology, and reverse transcription-polymerase chain reaction for messenger RNA expression. The result showed chrysin NPs treatment has counteracted oxidative stress, reduced neuronal apoptosis, and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1. In conclusion, our findings demonstrate that the neuroprotective effect of chrysin NPs against kindling-induced epilepsy might be escorted by the alleviation of oxidative stress through the Nrf2/antioxidant response element/HO-1 pathway signal pathway.

Butyrate alleviates PTZ-induced mitochondrial dysfunction, oxidative stress and neuron apoptosis in mice via Keap1/Nrf2/HO-1 pathway.

This study aims to evaluate the neuroprotective effect of sodium butyrate against the pentylenetetrazol (PTZ)-induced kindling epilepsy. Sodium butyrate (SB) (5, 10 and 20 mg/kg) and sodium valproate for 40 days and PTZ (37 mg/kg) injection every day were conducted for Kunming mice, to investigate seizure intensity and latency, oxidative stress parameters, mitochondrial structure and function, histopathology, and Keap1/Nrf2/HO-1 expressions. It is shown that seizure latency was effectively increased and the intensity of seizures decreased by treatment with sodium butyrate. It was also found to reverse the structural disruption of the mitochondria, reduce the ROS level and improve the levels of NAD + and ATP in the brains of epileptic mice. Furthermore, pretreatment with SB led to an increase in antioxidant enzyme activity (CAT, SOD and GSH-PX) in the brain as well as conferred a neuroprotective effect against neuron loss and apoptosis. The activation of Keap1/Nrf2/HO-1 signals was also identified, in which the antiepileptic effect of SB may be partially due to its anti-mitochondrial injury and neuroprotective activities. Accordingly, the results of a series of functional tests indicate a significant improvement of neurological function following SB treatment. In a mouse model of seizures, brain injury and neurological deficits can be attenuated by treatment with butyrate through the activation of Nrf2 pathway and the improvement of mitochondrial function.

Environmental enrichment alters neurobehavioral development following maternal immune activation in mice offspring with epilepsy.

Epilepsy is a chronic brain disease affecting millions of people worldwide. Anxiety-related disorders and cognitive deficits are common in patients with epilepsy. Previous studies have shown that maternal infection/immune activation renders children more vulnerable to neurological disorders later in life. Environmental enrichment has been suggested to improve seizures, anxiety, and cognitive impairment in animal models. The present study aimed to explore the effects of environmental enrichment on seizure scores, anxiety-like behavior, and cognitive deficits following maternal immune activation in offspring with epilepsy. Pregnant mice were treated with lipopolysaccharides-(LPS) or vehicle, and offspring were housed in normal or enriched environments during early adolescence to adulthood. To induce epilepsy, adult male and female offspring were treated with Pentylenetetrazol-(PTZ), and then anxiety-like behavior and cognitive functions were assessed. Tumor-necrosis-factor (TNF)-α and interleukin (IL) 10 were measured in the hippocampus of offspring. Maternal immune activation sex-dependently increased seizure scores in PTZ-treated offspring. Significant increases in anxiety-like behavior, cognitive impairment, and hippocampal TNF-α and IL-10 were also found following maternal immune activation in PTZ-treated offspring. However, there was no sex difference in these behavioral abnormalities in offspring. Environmental enrichment reversed the effects of maternal immune activation on behavioral and inflammatory parameters in PTZ-treated offspring. Overall, the present findings highlight the adverse effects of prenatal maternal immune activation on seizure susceptibility and psychiatric comorbidities in offspring. This study suggests that environmental enrichment may be used as a potential treatment approach for behavioral abnormalities following maternal immune activation in PTZ-treated offspring.

D-limonene Inhibits Pentylenetetrazole-Induced Seizure via Adenosine A2A Receptor Modulation on GABAergic Neuronal Activity.

BACKGROUND: Epilepsy is a chronic neurological disorder characterized by the recurrence of seizures. One-third of patients with epilepsy may not respond to antiseizure drugs. PURPOSE: We aimed to examine whether D-limonene, a cyclic monoterpene, exhibited any antiseizure activity in the pentylenetetrazole (PTZ)-induced kindling mouse model and in vitro. METHODS: PTZ kindling mouse model was established by administering PTZ (30 mg/kg) intraperitoneally to mice once every 48 h. We performed immunoblot blots, immunohistochemistry (IHC), and high-performance liquid chromatography (HPLC) analysis after the behavioral study. RESULTS: An acute injection of PTZ (60 mg/kg) induced seizure in mice, while pretreatment with D-limonene inhibited PTZ-induced seizure. Repeated administration of PTZ (30 mg/kg) increased the seizure score gradually in mice, which was reduced in D-limonene (10 mg/kg)-pretreated group. In addition, D-limonene treatment increased glutamate decarboxylase-67 (GAD-67) expression in the hippocampus. Axonal sprouting of hippocampal neurons after kindling was inhibited by D-limonene pretreatment. Moreover, D-limonene reduced the expression levels of Neuronal PAS Domain Protein 4 (Npas4)-induced by PTZ. Furthermore, the adenosine A2A antagonist SCH58261 and ZM241385 inhibited anticonvulsant activity and gamma-aminobutyric acid (GABA)ergic neurotransmission-induced by D-limonene. CONCLUSION: These results suggest that D-limonene exhibits anticonvulsant activity through modulation of adenosine A2A receptors on GABAergic neuronal function.

Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity.

Rationale: Dysfunction or reduced levels of EAAT2 have been documented in epilepsy. We previously demonstrated the antiepileptic effects of Hsp90 inhibitor 17AAG in temporal lobe epilepsy by preventing EAAT2 degradation. Because of the potential toxicities of 17AAG, this study aimed to identify an alternative Hsp90 inhibitor with better performance on Hsp90 inhibition, improved blood-brain barrier penetration and minimal toxicity. Methods: We used cell-based screening and animal models of epilepsy, including mouse models of epilepsy and Alzheimer's disease, and a cynomolgus monkey model of epilepsy, to evaluate the antiepileptic effects of new Hsp90 inhibitors. Results: In both primary cultured astrocytes and normal mice, HSP990 enhanced EAAT2 levels at a lower dose than other Hsp90 inhibitors. In epileptic mice, administration of 0.1 mg/kg HSP990 led to upregulation of EAAT2 and inhibition of spontaneous seizures. Additionally, HSP990 inhibited seizures and improved cognitive functions in the APPswe/PS1dE9 transgenic model of Alzheimer's disease. In a cynomolgus monkey model of temporal lobe epilepsy, oral administration of low-dose HSP990 completely suppressed epileptiform discharges for up to 12 months, with no sign of hepatic and renal toxicity. Conclusions: These results support further preclinical studies of HSP990 treatment for temporal lobe epilepsy.

Glutamatergic pathway in depressive-like behavior associated with pentylenetetrazole rat model of epilepsy with history of prolonged febrile seizures.

BACKGROUND: Depression is the most significant cause of suicide among neuropsychiatric illnesses. Major depression further affects the quality of life in an individual with epilepsy. The treatment of depression in an epileptic patient could be very challenging because of drug selection or the fact that some antiepileptic drugs are known to cause depression. It has been shown that in addition to the known involvement of the serotonergic pathway in depression, the glutamatergic system is also involved in the evolution of the disease, but this knowledge is limited. This study assessed if induction of epilepsy in rats will cause depressive-like behavior, alters the concentrations of metabotropic receptor 5 (mGluR5), glutamate transport protein (GLAST), glutamate synthase (GS) and brain derived neurotrophic factor (BDNF). MATERIALS AND METHOD: Epilepsy was induced in rats by injecting Pentylenetetrazole at 35 mg/kg every other day. At kindle, rats were subjected to sucrose preference test (SPT) and forced swim test (FST) and decapitated 4 h later. Hippocampal tissue was collected and the BDNF concentration was measured with ELISA; mGluR5 and GS protein expression was measured using western blot while amygdala tissue was used for GLAST expression with flow cytometry. RESULTS: Our results showed that epilepsy leads to depressive-like behavior in rats and alters the glutamatergic system. CONCLUSION: Therefore, we conclude that targeting the glutamate pathway may be a good strategy to alleviate depressive-like behavior associated with epilepsy.

Synthesis, anti-convulsant activity and molecular docking study of novel thiazole pyridazinone hybrid analogues.

Pyridazinone analogues have been known to be potential candidates for anticonvulsant agents. We have identified several pyridazinone-based anticonvulsant agents. As a continuation to our previous research, a series of hybrid pyridazinone-thiazole connected through amide linkage were designed and synthesized. Among these, compound SP-5F demonstrated significant anticonvulsant activity with median effective dose of 24.38 mg/kg (MES) and 88.23 mg/kg (scPTz). Results of GABA estimation showed a marked increase in the GABA level when compared with control. Molecular docking studies at the active site of GABA receptor, further confirmed the GABA modulatory effects of SP-5F.

Design, synthesis and docking studies of novel benzopyrone derivatives as anticonvulsants.

A series of coumarin derivatives 6-8, 9a-h, 11 and 13a, b -16a, b was synthesized and screened for their anticonvulsant profile. Screening of these analogues using the 'gold standard methods' revealed variable anticonvulsant potential with remarkable effects observed particularly in chemically-induced seizure test. Compounds 6, 7, 13b disclosed the highest potency among the series with 100% protection against scPTZ. Quantification study confirmed that compound 6 (ED50 0.238 mmol/kg) was the most active congener in the scPTZ model and was approximately 1.5 folds more potent than ethosuximide as reference drug Meanwhile, in the MES test, candidate drugs exhibited mild to moderate anticonvulsant efficacy, the highest of which was compound 14a, imparting 50% protection at 2.1 mmol/kg, followed by other compounds with activity ranging from 14 to 33%, as compared to diphenylhydantoin. Additionally, all candidate compounds were screened for acute neurotoxicity using the rotarod method to identify motor impairment, where almost all compounds passed the test. Further neurochemical investigation was performed to unravel the effect of the most active compound (6) on GABA level in mouse brain, where a significant elevation was evident by 4 and 1.4 folds with respect to that of the control and reference groups at p < 0.05. Molecular modeling study using Discovery Studio program was performed, where compound 6 exhibited good binding interaction with γ-aminobutyric acid aminotransferase (GABA-AT) enzyme and this was consistent with the attained experimental results.

Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide.

A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.

Salvinorin A Does Not Affect Seizure Threshold in Mice.

The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.

Anticonvulsant Activity of Essential Oil From Leaves of Zhumeria majdae (Rech.) in Mice: The Role of GABAA Neurotransmission and the Nitric Oxide Pathway.

The essential oil from the leaves of Zhumeria majdae Rech. (ZMEO) has been shown to have several beneficial effects in the clinic. In this work we examined the anticonvulsant activities of ZMEO in an experimental mouse model of seizure and aimed to identify any possible underlying mechanisms. ZMEO (5, 10, 20, and 40 mg/kg intraperitoneally (i.p.)) or diazepam, as the reference anticonvulsant drug (25, 50 and 100 µg/kg i.p.), were administered 60 minutes prior to pentylenetetrazol (PTZ) injection (intravenously (i.v.) or i.p.) and changes in threshold, latency, and frequency of clonic seizure were examined. The PTZ i.p.-induced model of seizure was also applied for examining the protective effects of ZMEO pretreatment against PTZ-induced mortality. In some studies, the anticonvulsant effect of the combination of diazepam and ZMEO was also studied. The protective effects of ZMEO against hindlimb tonic extensions (HLTEs) were also examined by maximal electroshock (MES) seizure testing. The γ-aminobutyric acid (GABA)ergic mechanism and nitric oxide (NO) pathway involvement in anticonvulsant activity of ZMEO were assessed by pretreating animals with flumazenil, Nω -nitro-L-arginine methyl ester (L-NAME), aminoguanidine, and L-arginine in a PTZ-induced model of seizure. Administration of 20 mg/kg ZMEO significantly increased chronic seizure threshold and latency while reducing frequency of convulsions and mortality in the PTZ-induced model. In the doses studied, ZMEO could not protect mice from HLTE and mortality induced by MES. Pretreatment with L-arginine and diazepam potentiated the anticonvulsant effects of ZMEO, whereas pretreatment with L-NAME, aminoguanidine, and flumazenil reversed anticonvulsant activity. The anticonvulsant activity of ZMEO may be mediated in part through a GABAergic mechanism and the NO signaling pathway.